Achieving hepatitis B e antigen (HBeAg) seroconversion is a satisfactory endpoint during antiviral treatment for chronic hepatitis B (CHB). This study aimed to develop and validate a novel scoring system to predict HBeAg seroconversion during entecavir (ETV) treatment. A total of 526 patients with HBeAg-positive CHB treated with ETV for at least 1 year were randomly assigned to the training and validation cohorts. Baseline parameters including hepatitis B virus DNA, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and alanine aminotransferase level were quantified. Patients who achieved HBeAg seroconversion were compared with those without HBeAg seroconversion. A prediction model was established to predict HBeAg seroconversion during ETV treatment. After a median follow up of 2.67 years, 93 (36.0%) and 87 (32.5%) patients in the training and validation cohorts developed HBeAg seroconversion. A prediction score composed of age, HBsAg and HBcAb quantification was derived. Areas under receiver operating characteristic curve at 5 years of this prediction score were 0.70 and 0.72 in the training and validation cohorts. By using the dual cutoff values of 0.28 and 0.58, the model was endowed with high sensitivity and specificity to exclude or identify patients developing HBeAg seroconversion (90.3% sensitivity and 90.2% specificity in the training cohort as well as 92.8% sensitivity and 84.4% specificity in the validation cohort, respectively). A novel prediction score that uses baseline clinical variables was developed and validated. The score accurately estimates the probabilities of developing HBeAg seroconversion at 5-years ETV therapy in patients with CHB.

Hepatitis B virus (HBV) can be found in ovarian tissues. This study compared HBV DNA levels in follicular fluid collected during oocyte retrieval with paired serum samples in HBV carriers after ovarian stimulation during IVF treatment for infertility. Sixty-four HBV carrier women referred to the Assisted Reproductive Units of two Hong Kong hospitals were recruited. At oocyte retrieval, the follicular fluid aspirated from the first follicle was collected for study. In 22 women, the first follicular fluid sample from both ovaries was similarly collected and studied. These women were also tested for liver function test and HBeAg. In 28 (43.8%) women, HBV DNA was detected in follicular fluid and the level correlated with serum levels (Spearman's correlation P < .001). There was concordant detection of HBV DNA in both ovaries, and the levels were significantly correlated (Spearman's correlation P = .029). In 40% of women with FF HBV DNA, the follicular fluid:serum ratio was >1.0, suggesting stimulation of HBV replication. These women also had significantly different liver function test results. Increased HBV replication exists in 40% of women with HBV DNA detected in follicular undergoing ovarian stimulation during IVF treatment.

Nucleos(t)ide analogues (NA) are effective in suppressing hepatitis B virus (HBV) replication, but most patients require long-term treatment. This study aimed to investigate switching to peginterferon as a strategy to stop NA. Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients who developed HBeAg seroconversion during NA treatment were studied. All patients received open-label peginterferon alfa-2a 180 μg/wk for 48 weeks, and NA was stopped at week 4 of peginterferon treatment. The primary endpoint was sustained response, which was defined as negative HBeAg, positive anti-HBe and HBV DNA <2000 IU/mL at week 72. Other secondary endpoints including HBsAg loss at week 72 were also studied. Forty-one patients treated with entecavir for 56 ± 23 months were recruited. Sustained response was achieved in 30 patients (73%, 95% confidence interval 58%-84%). At week 72, 31 (76%) patients had HBeAg seroconversion, 56 (23%) patients had undetectable HBV DNA, 31 (76%) patients had normal ALT, and 6 patients (15%) had HBsAg loss. Baseline HBsAg level was the best predictor for both sustained response and HBsAg loss; the best HBsAg cut-off for sustained response was <1500 IU/mL and that for HBsAg loss was <500 IU/mL by receiver operating characteristic curve analysis. Twenty-two of 25 (88%) patients with baseline HBsAg <1500 IU/mL had sustained response. Five of 10 (50%) patients with baseline HBsAg <500 IU/mL developed HBsAg loss. Switching to peginterferon can be considered as a treatment option in NA-treated patients with HBeAg seroconversion, particularly among those with lower HBsAg levels.

Metabolic syndrome is an independent risk factor of liver cirrhosis in chronic hepatitis B (CHB). Whether metabolic syndrome affects the long-term prognosis of CHB patients in terms of hepatic events, cardiovascular events, and death remains unknown. We aimed to determine the incidences of hepatic events, cardiovascular events, and death in CHB patients with or without metabolic syndrome. From 2006 to 2008, we prospectively recruited 1,466 CHB patients for liver stiffness measurement (LSM) with transient elastography together with detailed metabolic profiling as baseline assessment. Patients were prospectively followed for any clinical events. The impact of LSM and metabolic syndrome on hepatic events, cardiovascular events, and death was evaluated. At baseline visit, the mean age was 46 ± 12 years, LSM value was 8.4 ± 6.3 kPa, and 188 patients (12.8%) had metabolic syndrome. At a mean follow-up of 88 ± 20 months, 93 and 44 patients developed hepatic and cardiovascular events, respectively; 70 patients died. Patients with baseline LSM >8.0 kPa had higher cumulative probability of hepatic events than those with LSM ≤8.0kPa at 8 years (12.3% versus 3.1%, P < 0.001). Patients with metabolic syndrome had higher cumulative probability of cardiovascular events than those without (8.0% versus 2.1%, P < 0.001). High LSM had no impact on cardiovascular events; neither did metabolic syndrome on hepatic events. LSM >8.0 kPa but not metabolic syndrome was an independent risk factor of death, with adjusted hazard ratios of 1.9 (95% confidence interval 1.1-3.2, P = 0.023) and 1.3 (95% confidence interval 0.8-2.4, P = 0.310), respectively.

Metabolic syndrome increased the risk of cardiovascular events but not hepatic events and death; LSM was the important risk factor of hepatic events and death in CHB patients. (Hepatology 2016;64:1507-1517).

we aimed to investigate the accuracy of liver (LSM) spleen stiffness measurement (SSM) with transient elastography (TE) to predict varices in the presence of non-selective beta-blockers (NSBB).

In this cross-sectional study of consecutive patients with chronic hepatitis B (CHB) and cirrhosis, all patients underwent TE and upper endoscopic examinations. LSM and SSM in predicting varices in patients receiving and not receiving NSBB were evaluated.

Altogether 144 CHB patients (29 receiving NSBB; 35 with any varices, 31 and 11 with esophageal and gastric varices, respectively) were recruited. Their mean LSM and SSM were 13.3 ± 9.0 kPa and 32.8 ± 19.2 kPa, respectively. The correlation between LSM and SSM was better in the NSBB subgroup (r = 0.525, P = 0.003) than its counterpart (r = 0.329, P  < 0.001). The area under receiver operating characteristic curve (AUROC) of LSM and SSM for any varices was 0.675 and 0.685 (P = 0.002 and 0.001), respectively. SSM of 18.9 kPa had a negative predictive value of 92.1% and negative likelihood ratio of 0.27 for ruling out any varices; and SSM of 54.9 kPa had a positive predictive value of 56.5% and a positive likelihood ratio of 4.05 to rule in varices. The AUROC of LSM for varices was 0.742 and 0.549 in patients with or without NSBB, respectively; the corresponding AUROC of SSM was 0.572 and 0.603, respectively.

SSM only has modest accuracy to predict varices independent of NSBB use. An SSM cutoff value of 18.9 kPa may be adopted to achieve a high negative predictive value to rule out varices.

Hepatitis B s antigen (HBsAg) seroclearance is regarded as the optimal virological end-point.

To investigate the dynamic changes in serum cytokine levels around the time of HBsAg seroclearance.

This was a case-control study. Consecutive patients with chronic hepatitis B (CHB) who lost HBsAg were matched with those remained positive for HBsAg with same age, gender, HBeAg status and presence of cirrhosis in 1:2 ratio. Relevant serum cytokines [interleukin (IL)-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, IL-15, IL-21 interferon-γ, tumour necrosis factor-α (TNF-α), granulocyte macrophage colony-stimulating factor (GM-CSF) and interferon-inducible protein 10 (IP-10)] were assayed at the time (Year 0) and 3 years before (Year -3) HBsAg seroclearance.

Seventy-one and 142 CHB patients who did and did not achieve HBsAg seroclearance were included. Mean age was 48 ± 11 years; 76% were male, 20% had positive HBeAg, 99 (46%) patients received anti-viral therapy, and mean baseline HBV DNA was 3.78 ± 2.28 log IU/mL vs. 4.36 ± 2.13 log IU/mL respectively (P = 0.05). In those who achieved HBsAg seroclearance, serum IL-15 and GM-CSF levels decreased significantly from Year -3 to Year 0 (P = 0.017 and 0.05 respectively). When compared to controls, only serum IP-10 level was significantly lower at Year 0 than at Year -3 in patients with HBsAg seroclearance. Lower serum IP-10 level at Year 0 was the only factor associated with HBsAg seroclearance. There was no correlation between serum IP-10 and HBsAg levels around the time of HBsAg seroclearance.

Lower serum IP-10 level at Year 0 was the only factor associated with HBsAg seroclearance.

Tenofovir disoproxil fumarate has been used in chronic hepatitis B patients with suboptimal virologic response to nucleos(t)ide analogues. The efficacy of tenofovir switch therapy has not been well studied in Asian patients.

To evaluate the efficacy of tenofovir switch therapy in nucleos(t)ide-experienced patients, and identify the factors associated with treatment response of tenofovir switch therapy.

Nucleos(t)ide-experienced hepatitis B e antigen-positive and -negative patients prescribed with tenofovir were retrospectively identified and recruited for prospective analysis. Hepatitis B virus (HBV) DNA and other biochemical parameters were monitored in regular 3-6 monthly follow-up visits. Primary efficacy endpoint was maintained-virologic response with tenofovir switch therapy, defined as undetectable HBV DNA (<20 IU/mL) until the last follow-up visit.

An overall of 214/252 (84.9%) patients achieved maintained-virologic response after 22 (7-55) months of tenofovir switch therapy. On multivariate analysis, a lower HBV DNA level at the time of switching to tenofovir was an independent factor associated with treatment efficacy. Maintained-virologic response after switching to tenofovir was achieved in 177/190 (93.2%) patients with HBV DNA <20 000 IU/mL vs. 37/62 (59.7%) patients with HBV DNA ≥20 000 IU/mL (P < 0.001). Absence of genotypic resistance to lamivudine or adefovir dipivoxil was not associated with improved treatment outcome.

Tenofovir switch therapy is an effective treatment strategy in nucleos(t)ide-experienced chronic hepatitis B patients. However, in patients with HBV DNA ≥20 000 IU/mL at the time of switching to tenofovir, the chance of achieving maintained undetectable HBV DNA is significantly reduced.

Vitamin D is an immunomodulator that might be involved in the pathogenesis of viral hepatitis. We investigated the effects of vitamin D deficiency on long-term outcomes of patients with chronic hepatitis B (CHB).

We performed a prospective cohort study of 426 patients with CHB (65% male; mean age, 41 ± 13 years), who were enrolled from 1997 through 2000. Serum levels of 25-hydroxycholecalciferol (25(OH)D3) were measured on study enrollment (baseline). Patients were followed for 159 ± 46 months until last clinic visit or death; approximately 33% received antiviral therapy during the follow-up period. The primary outcome was a clinical event (hepatocellular carcinoma, complications of cirrhosis, or death).

At baseline, the patients' mean serum level of hepatitis B virus DNA was 5.0 ± 2.1 log10 IU/mL; their mean level of 25(OH)D3 was 24.3 ± 9.4 ng/mL, and 348 patients (82%) had vitamin D deficiency (<32 ng/mL). Serum levels of 25(OH)D3 did not correlate with cirrhosis or viral load. Ninety-seven patients (22.8%) developed clinical events by a mean time of 118 ± 60 months after study enrollment. Patients who developed clinical events had lower baseline serum levels of 25(OH)D3 (23.2 ± 10.4 ng/mL) than patients who did not (28.2 ± 9.3 ng/mL, P < .001). Low baseline serum 25(OH)D3 was an independent factor associated with clinical events after adjustment for sex, age, and cirrhosis. The adjusted hazard ratio of vitamin D deficiency for clinical events was 1.90 (95% confidence interval [CI], 1.06-2.43; P = .04). The 15-year cumulative incidence rate of clinical events among patients with vitamin D deficiency was 25.5% (95% CI, 23.1%-27.9%), compared with 11.1% (95% CI, 7.4%-14.8%) in patients with normal serum levels of 25(OH)D3.

Vitamin D deficiency is common among patients with CHB and is associated with adverse clinical outcomes.

The prognostic role of noninvasive assessments of liver fibrosis has been evolving. Our aim was to investigate the prognostic value of liver stiffness measurement (LSM) with transient elastography and serum-based Hui index to predict hepatic events and deaths in chronic hepatitis B (CHB) patients.

The main prospective cohort included 1555 consecutive CHB patients referred for transient elastography examination; a subgroup of 980 patients underwent follow-up assessments at least 3 years later formed the serial cohort. Cox proportional hazard model was performed to determine the relationship of LSM, Hui index and other clinical variables with hepatic events and deaths.

During a mean follow-up of 69 ± 9 months, 119 patients (7.6%) developed hepatic events or deaths. Hepatic event-free survival was significantly decreased with increasing stages of LSM and Hui index. The 5-year cumulative probability of hepatic event-free survival of patients of Stage 1-7 of LSM were 99.3%, 98.8%, 95.7%, 90.9%, 89.6%, 74.6%, and 50.0%, respectively; that of Stage 1 to 3 of Hui index were 98.2%, 93.1%, and 77.5%, respectively. Independent predictors of hepatic event-free survival were age, baseline LSM, and follow-up Hui index. Serum ALT and body mass index affected the accuracy of prediction by LSM. Patients remained early stages of LSM or Hui index at follow-up visit had better survival compared to those remained at late stages.

Baseline and change in noninvasive parameters of liver fibrosis, LSM and Hui index, are accurate to predict hepatic event-free survival in CHB patients.

The effect of antiviral therapy on the post-hepatectomy long-term survival in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains uncertain.

To evaluate the effect of antiviral therapy on post-hepatectomy survival and recurrence in patients with HBV-related HCC.

This was a prospective-retrospective study of a total of 404 patients who underwent hepatectomy for HBV-related HCC in a tertiary academic hospital. Data on patient and tumour characteristics, tumour recurrence, treatment for recurrence and survival were compared between antiviral and no antiviral groups.

Patient's and tumour characteristics were comparable between the two groups, except a higher proportion of patients with cirrhosis in the antiviral group. With a mean follow-up time of 52.4 months, antiviral group had a better 5-year overall survival (66.7% vs. 56.0%, P = 0.001) while there was no significant difference in the 5-year disease-free survival (44.7% vs. 38.1%, P = 0.166). Use of antiviral therapy was associated with better liver function reserve at the time of recurrence and a greater proportion of patients could receive curative treatment for recurrence (38.5% vs. 24.3%, P = 0.041). There was no significant different in the hazard ratios of patients who started antiviral therapy before or after operation (P = 0.054).

Use of antiviral therapy improves the long-term post-hepatectomy survival in patients with HBV-related HCC. With a better liver function reserve at the time of recurrence, a greater proportion of patients in antiviral group could receive curative treatment for recurrence.

Kinetics of serum hepatitis B surface antigen (HBsAg) level in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients presented with severe reactivation and received oral antiviral therapy is unknown. We aimed to investigate the kinetics of HBsAg level among these patients.

HBeAg-negative patients on antiviral therapy with follow-up for 2 years were studied. Those presented with severe reactivation (alanine aminotransferase [ALT] ≥5 times of normal) were compared to those with mild hepatitis. Serum HBsAg level was measured by Elecsys HBsAg II Quant assay (Roche) at baseline and 6-monthly.

A total of 192 (74 severe reactivation) patients were studied. Eighty-one (42%), 74 (39%) and 37 (19%) patients were on lamivudine, entecavir and telbivudine, respectively. Forty-four (23%) patients had early HBsAg decline, that is, ≥0.5 log10 reduction, at month 6. Patients with severe reactivation had higher serum baseline ALT (1,415 ±897 versus 73 ±39 IU/l), HBV DNA (6.4 ±1.6 versus 5.2 ±1.2 log10 IU/ml) and HBsAg (3.3 ±1.0 versus 2.9 ±0.6 log10 IU/ml), as well as an earlier HBsAg decline (50% versus 6%; all P<0.001) than those without. The HBsAg change of patients with severe reactivation was higher at months 0-6 (-0.58 ±-1.26 versus -0.01 ±-0.26 log10 IU/ml; P<0.001) but then became comparable from months 6-24 (-0.19 ±-0.60 versus -0.13 ±-0.19 log10 IU/ml; P=0.85), compared to those presented with mild hepatitis.

Patients who presented with severe reactivation of HBeAg-negative hepatitis were more likely to develop early HBsAg decline during antiviral therapy. It may indicate a transient strong immune clearance with rapid initial reduction in serum HBsAg, which cannot be sustained due to a faster clearance of serum HBsAg.

Metabolic syndrome is a known risk factor of cirrhosis in chronic hepatitis B (CHB).

To investigate the effects of coincidental metabolic syndrome on liver fibrosis progression in treatment-naïve CHB patients.

A total of 1466 CHB patients underwent liver stiffness measurement (LSM) by transient elastography in 2006-2008; 663 patients remained treatment-naïve and had second LSM in 2010-2012. Liver fibrosis progression was defined as an increase in LSM ≥30% at the second assessment. The impact of coincidental metabolic syndrome and its factors on liver fibrosis progression were evaluated after adjustment for viral load and hepatitis activity.

At baseline, the mean age was 43 ± 12 years, 55% were males, serum alanine aminotransferase (ALT) was 44 ± 40 IU/L, HBV DNA was 4.0 ± 2.0 log IU/mL and LSM was 6.3 ± 3.6 kPa. Metabolic syndrome was diagnosed in 80 (12%) and 142 (21%) patients at baseline and follow-up visit, respectively; 84 (13%) and 22 (3%) patients had coincidental and resolved metabolic syndrome respectively. After an interval of 44 ± 7 months, 107 (16%) patients developed liver fibrosis progression. Coincidental metabolic syndrome [adjusted odds ratio (aOR) 2.0, 95% confidence interval (CI) 1.1-3.5, P = 0.015], central obesity (aOR 2.0, 95% CI 1.0-4.1, P = 0.05) and low level of high-density lipoprotein cholesterol (aOR 1.9, 95% CI 1.0-3.7, P = 0.04) were associated with liver fibrosis progression independent of change in viral load and ALT level. The effects of coincidental metabolic syndrome were most apparent in the immune-tolerant phase.

Coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B infection, independent of viral load and hepatitis activity.

Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) surveillance, which is criticized as neither sensitive nor specific in active hepatitis and liver cirrhosis. The aim of this study was to determine the performance of AFP as a tumor marker for HCC in entecavir-treated patients with chronic hepatitis B (CHB). This was a retrospective-prospective cohort study of 1,531 entecavir-treated patients under regular HCC surveillance with AFP and ultrasonography. Mean age was 52 ± 12 years; 1,099 (72%) patients were male and 332 (21.7%) had clinical evidence of cirrhosis. At a mean follow-up of 51 ± 13 months, 57 (2.9%) patients developed HCC (median size: 3.3 cm). AFP fluctuated with alanine aminotransferase (ALT) and peaked at the time of starting entecavir, then gradually decreased after. AFP started to increase 6 months before the diagnosis of HCC. The receiver operator characteristic curve (AUROC) of AFP was highest at the time of HCC diagnosis (0.85; 95% confidence interval [CI]: 0.73-0.98) and remained satisfactory at 3 (0.82; 95% CI: 0.73-0.91) and 6 months (0.79; 95% CI: 0.69-0.89) before the diagnosis. Using the conventional AFP cut-off (20 μg/L) at month 0, the sensitivity and specificity to diagnose HCC were 38.6% and 98.9%, respectively. Adopting the lower cut-off value (6 μg/L) of AFP level at month 0, sensitivity was increased to 80.7%, whereas specificity was decreased to 80.4%.

On-treatment AFP is a specific tumor marker for HCC in CHB patients receiving entecavir therapy. Adopting a lower cut-off value of AFP level at 6 μg/L would significantly increase the sensitivity for HCC detection.

CU-HCC score is accurate to predict hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. However, diagnosis of cirrhosis may be incorrect based on ultrasonography, leading to some errors in HCC prediction. This study aimed to evaluate the accuracy of LSM-HCC score, refined from CU-HCC score with liver stiffness measurement (LSM) using transient elastography to predict HCC.

A prospective cohort study of 1555 consecutive CHB patients referred for transient elastography examination; 1035 and 520 patients randomly assigned to training and validation cohorts, respectively. Clinical cirrhosis of CU-HCC score was substituted by LSM and analyzed with multivariable Cox regression analysis with other parameters.

During a mean follow-up of 69 months, 38 patients (3.7%) in the training cohort and 17 patients (3.4%) in the validation cohort developed HCC. A new LSM-HCC score composed of LSM, age, serum albumin and hepatitis B virus (HBV) DNA levels were derived, which ranges from 0 to 30. Areas under receiver operating characteristic curves of LSM-HCC score were higher than those of CU-HCC score (0.83-0.89 vs. 0.75-0.81). By applying the cutoff value of 11, the score excluded future HCC with high negative predictive value (99.4%-100%) at 5 years.

LSM-HCC score constructed from LSM, age, serum albumin and HBV DNA level is accurate to predict HCC in CHB patients.

The accuracy of Enhanced Liver Fibrosis (ELF; ADVIA Centaur, Siemens Healthcare Diagnostics, Tarrytown, NY, USA) in assessing liver fibrosis in chronic hepatitis B (CHB) is to be determined.

To derive and validate a combined ELF-liver stiffness measurement (LSM) algorithm to predict advanced fibrosis in CHB patients.

Using the data of a previously reported cohort of 238 CHB patients, an ALT-based LSM algorithm for liver fibrosis was used as a training cohort to evaluate the performance of ELF against liver histology. The best combined ELF-LSM algorithm was then validated in new cohort of 85 CHB patients not previously reported.

In the training cohort, LSM has better performance of diagnosing advanced (≥F3) fibrosis (area under the receiver operating characteristics curve [AUROC] 0.83, 95% confidence interval [CI 0.76-0.91] than ELF (AUROC 0.69, 95% CI 0.63-0.75). The optimal cut-off values of ELF were 8.4 to exclude advanced fibrosis, and 10.8 to confirm advanced fibrosis. In the training cohort, an ELF ≤ 8.4 had a sensitivity of 95% to exclude advanced fibrosis; an ELF > 10.8 had a specificity of 92% to confirm advanced fibrosis. In the combined algorithm, low ELF or low LSM could be used to exclude advanced fibrosis as both of them had high sensitivity (≥90%). To confirm advanced fibrosis, agreement between high ELF and high LSM could improve the negative predictive value specificity (from 65% and 74% to 80%).

An Enhanced Liver Fibrosis - liver stiffness measurement algorithm could improve the accuracy of prediction of either ELF or LSM alone. Liver biopsy could be correctly avoided in approximately 60% of patients.

The European Association for the Study of the Liver (EASL) defines the inactive hepatitis B virus (HBV) carrier state based on HBV DNA and alanine aminotransferase (ALT) levels. This study aimed to evaluate the risk of disease progression in such patients.

Three hundred sixty-one patients negative for hepatitis B e antigen (HBeAg) with HBV DNA levels < 20,000 IU/mL and normal ALT and without advanced fibrosis at baseline underwent liver stiffness measurement (LSM) by transient elastography between 2006 and 2008 and again between 2010 and 2012. Liver fibrosis progression was defined as an increase in LSM by 30% or more at the second assessment to levels suggestive of advanced fibrosis.

At baseline, the mean age was 48 ± 11 years and 51% were males; ALT level was 28 ± 11 IU/L, HBV DNA level was 2.7 ± 1.0 log10  IU/mL, and LSM was 5.4 ± 1.5 kPa. After an interval of 44 ± 7 months, liver fibrosis progression was observed in 10 (2.8%) patients, and 49 (13.6%) started antiviral therapy. Gender, age, and levels of ALT, HBV DNA, and HBsAg were shown not to be associated with liver fibrosis progression. Among 244 patients with baseline HBV DNA < 2000 IU/mL, 2.9% had liver fibrosis progression, 8.2% started antiviral therapy, and 4.1% had HBV DNA ≥ 20,000 IU/mL during follow-up. Corresponding figures in 117 patients with baseline HBV DNA levels of 2000-20,000 IU/mL were 2.6%, 24.8%, and 7.7%, respectively (P = 1.0, < 0.001 and = 0.21 respectively).

Liver fibrosis progression within 3-4 years is rare in HBeAg-negative patients with HBV DNA <20,000 IU/mL and normal ALT, but a significant proportion of patients develop treatment indications during follow-up. The study supports the EASL's definition of inactive carriers and its recommendation of regular monitoring.

Entecavir is a potent antiviral agent with high genetic barrier to resistance, hence it is currently recommended as first-line antiviral therapy for chronic hepatitis B (CHB). The aim of this study was to investigate the efficacy of entecavir on clinical outcomes and deaths. It was a retrospective-prospective cohort study based on two cohorts of patients. The entecavir cohort included consecutive CHB patients who had received entecavir 0.5 mg/day for at least 12 months. The historical control cohort included untreated patients recruited since 1997 who underwent routine clinical care. The primary outcome was the 5-year cumulative probability of hepatic events, defined as any cirrhotic complications, hepatocellular carcinoma (HCC), and/or liver-related mortality. A total of 1,446 entecavir-treated patients (72% men; age, 51 ± 12 years; follow-up, 36 ± 13 months) and 424 treatment-naïve patients (65% men; age, 41 ± 13 years; follow-up, 114 ± 31 months) were studied. Overall, there was no difference in hepatic events between the entecavir and control cohorts. Among patients with liver cirrhosis (482 entecavir-treated, 69 treatment-naïve), entecavir-treated patients had reduced risks of all clinical outcomes when compared with treatment-naïve patients with cirrhosis after adjusted for model for end-stage liver disease score: hepatic events (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.34-0.78; P = 0.002), HCC (HR, 0.55; 95% CI, 0.31-0.99; P = 0.049), liver-related mortality (HR, 0.26; 95% CI, 0.13-0.55; P < 0.001), and all-cause mortality (HR, 0.34; 95% CI, 0.18-0.62; P < 0.001). Entecavir-treated patients with cirrhosis who failed to achieve undetectable hepatitis B virus DNA (105/482 [22%]) had comparable risk of hepatic events as the untreated patients.

Entecavir therapy reduces the risks of hepatic events, HCC, liver-related and all-cause mortality of CHB patients with liver cirrhosis in 5 years, particularly among those who had maintained viral suppression.

Chronic hepatitis B patients in immune-reactive hepatitis B e antigen (HBeAg)-positive phase may have more rapid progression than those in immune-tolerant phase. We aimed to evaluate the risk of liver fibrosis progression in HBeAg-positive patients at different phases.

Two hundred forty-seven HBeAg-positive patients without advanced fibrosis at baseline underwent liver stiffness measurement (LSM) by transient elastography in 2006-2008 and again in 2010-2012. Liver fibrosis progression was defined as increase in LSM by 30% or more to levels suggestive of advanced fibrosis at the second assessment.

At baseline, the mean age was 38 ± 11 years, 58% were males, alanine aminotransferase (ALT) was 65 ± 52 IU/L, hepatitis B virus DNA was 4.2 ± 1.2 log IU/mL, and LSM was 6.3 ± 2.1 kPa. At an interval of 42 ± 6 months, 13 patients (5.2%) developed liver fibrosis progression, and 106 patients (42.9%) required antiviral therapy. None of the clinical parameters (e.g., gender, age, ALT, hepatitis B virus DNA, hepatitis B surface antigen level, etc.) was associated with liver fibrosis progression. Among 74 and 137 patients in immune-tolerant and immune-reactive phase, 4.1% and 6.6% had liver fibrosis progression, and 12.2% and 67.2% received antiviral therapy respectively (P = 0.45 and P < 0.001). Immune-tolerant patients with low-normal (< 0.5× upper limit of normal) or high-normal ALT (0.5-1× upper limit of normal) also had similar risk of liver fibrosis progression (5.7% vs. 2.6%; P = 0.49).

Liver fibrosis progression is uncommon in HBeAg-positive patients. Patients in immune-reactive phase treated with antiviral therapy did not have increased risk of liver fibrosis progression.

For hepatitis B e antigen (HBeAg)-positive patients, continuing therapy (consolidation) for 6-12 months before cessation of nucleos(t)ide analogues (NAs) was recommended. This study aimed to investigate whether a longer period of lamivudine consolidation therapy leads to better outcomes and the clinical factors associated with response.

Combined response [HBeAg seroconversion and undetectable serum hepatitis B virus (HBV) DNA by PCR assay] 6 months [end of follow-up (EOF)] after cessation of therapy was assessed in 101 HBeAg-positive chronically infected patients who received continued long-term lamivudine treatment and achieved a combined response at the end of treatment.

The rate of combined response at EOF was 40.6%. A lower pretreatment HBV DNA level, a longer duration of consolidation therapy, pretreatment hepatitis B surface antigen titre <1500 IU/mL and a higher proportion of consolidation duration of >18 months were significantly associated with combined response. A lower pretreatment HBV DNA level and a longer duration of consolidation therapy were independent factors associated with combined response at EOF by multivariate logistic regression analyses. The rate of combined response was 71.4%, 39.0% and 25.6% in patients with consolidation duration of >18 months, 12-18 months and <12 months, respectively (P = 0.001). Consolidation therapy for >18 months achieved a significantly higher rate of combined response at EOF in patients achieving combined response within or after 6 months.

Consolidation therapy for >18 months significantly improved the outcome of lamivudine therapy, particularly for patients who achieved a combined response after 6 months.

Little is known about the validity of hepatocellular carcinoma (HCC) risk scores derived from treatment-naïve patients with chronic hepatitis B for patients treated with entecavir.

We performed a retrospective-prospective cohort study of 1531 patients with chronic hepatitis B (age, 51 ± 12 years; 1099 male; 332 with clinical cirrhosis) who were treated with entecavir 0.5 mg daily for at least 12 months at Prince of Wales Hospital in Hong Kong from December 2005 to August 2012. The patients were assessed once every 3 to 6 months for symptoms, drug history, and adherence; blood samples were collected for biochemical analyses. We validated 3 HCC risk scores (CU-HCC, GAG-HCC, and REACH-B scores) based on data collected when patients began treatment with entecavir and 2 years later.

After 42 ± 13 months of follow-up, 47 patients (2.9%) developed HCC. The 5-year cumulative incidence of HCC was 4.3% (95% confidence interval [CI], 3.6%-5.0%). Older age, presence of cirrhosis, and virologic remission after 24 months or more of therapy were independently associated with HCC in the entire cohort; advanced age and hypoalbuminemia were associated with HCC in patients without cirrhosis. The area under the receiver operating characteristic curves (AUCs) for baseline CU-HCC, GAG-HCC, and REACH-B scores for HCC were 0.80 (95% CI, 0.75-0.86), 0.76 (95% CI, 0.70-0.82), and 0.71 (95% CI, 0.62-0.81), respectively; the time-dependent AUCs 1 to 4 years after patients started treatment were comparable to those at baseline. The cutoff value of the baseline CU-HCC score identified patients who would develop HCC with 93.6% sensitivity and 47.8% specificity, the baseline GAG-HCC score with 55.3% sensitivity and 78.9% specificity, and the baseline REACH-B score with 95.2% sensitivity and 16.5% specificity. Compared with patients with CU-HCC scores <5 at baseline, those with CU-HCC scores that either decreased from ≥5 to <5 or remained ≥5 had a higher risk of HCC (5-year cumulative incidences, 0% vs 3.9% and 7.3%; P = .002 and P < .001, respectively).

The CU-HCC, GAG-HCC, and REACH-B HCC risk scores accurately predict which patients with chronic hepatitis B treated with entecavir will develop HCC.

The roadmap concept suggests the use of on-treatment HBV DNA to guide treatment strategy of chronic hepatitis B patients treated by telbivudine. Our aim was to validate the roadmap approach of entecavir switch therapy in patients with incomplete response to telbivudine.

Consecutive chronic hepatitis B patients on telbivudine monotherapy were studied. Incomplete virological response was defined as detectable HBV DNA after 6-12 months of treatment. Maintained virological response was defined as undetectable HBV DNA until the last follow-up.

Among the 79 patients on telbivudine, 39 (49%) had undetectable HBV DNA after 6-12 months of telbivudine treatment and 40 (51%) had incomplete virological response. In total, 33 incomplete responders switched to entecavir at 11 months (6-23), and 26 (79%) achieved maintained virological response after 25 months (4-46). Low HBV DNA level before switch therapy was the independent factor associated with maintained virological response to entecavir (P=0.01). A total of 24 of 25 (96%) patients with HBV DNA<2,000 IU/ml, versus 2 of 8 (25%) patients with HBV DNA≥2,000 IU/ml, had maintained virological response after switching to entecavir. Although rtM204I and/or rtL180M was detected in 3 of 7 patients with incomplete virological response to entecavir, none of the patients with HBV DNA<2,000 IU/ml during telbivudine treatment harboured these amino acid substitutions.

Roadmap approach using entecavir switch at month 6-12 among incomplete responders to telbivudine is recommended if the HBV DNA is <2,000 IU/ml at the time of switching.

On-treatment monitoring of serum hepatitis B virus (HBV) DNA to guide treatment strategy for patients on entecavir has received little attention.

To investigate the predictive value of on-treatment HBV DNA levels for responses to entecavir.

This was a retrospective cohort study among nucleos(t)ide analogue-naïve HBV-infected patients on entecavir with a minimum follow-up of 2 years. Maintained virological suppression was defined as undetectable HBV DNA (<20 IU/mL) until the last visit. Genotypic drug resistance was screened by using the INNO-LiPA DR assay.

A total of 440 chronic hepatitis B patients (160 HBeAg-positive) followed for 34 ± 9 months were included. The cumulative probability of maintained virological suppression at year 1, 2 and 3 were 76.5%, 83.0% and 88.3% respectively. On multivariate analysis, lower baseline HBV DNA, undetectable HBV DNA at month 12 and negative HBeAg were the independent predictors of maintained virological suppression. M12 responders (who had undetectable HBV DNA at month 12) had higher probability of maintained virological suppression at 3 years (99.1%) as compared to non responders (57.5%; P < 0.001). The cumulative probability of HBeAg-seroconversion at year 1, 2 and 3 were 19.0%, 27.2% and 33.5% respectively. M12 responders had higher probability of HBeAg-seroconversion at 3 years (43.2%) than the non responders (19.0%; P = 0.003). M12 responders had lower probability of drug resistance at 3 years (0%) than the non responders (2.6%; P = 0.004).

Month 12 HBV DNA responses could predict the probability of maintained virological suppression, HBeAg-seroconversion and risk of drug resistance among patients on entecavir treatment at 3 years.

The timing of antiviral therapy cessation in hepatitis B e antigen (HBeAg)-negative patients is controversial. Here, we aimed to investigate the role of HBV DNA and hepatitis B surface antigen (HBsAg) monitoring to predict off-treatment sustained response.

A total of 53 HBeAg-negative chronic hepatitis B patients who received lamivudine for 34 ±23 (range 12-76) months and had lamivudine stopped for 47 ±35 months were studied. Primary outcome was sustained response, defined as HBV DNA≤200 IU/ml, at 12 months post-treatment (SR-12).

A total of 9 (17%) patients achieved SR-12. HBV DNA at baseline, month 6 and end of treatment had no association with SR-12. HBsAg levels tended to decrease more significantly during treatment among SR-12 responders. At the end of treatment, both HBsAg ≤2 log IU/ml and reduction by >1 log from baseline had sensitivity, specificity, positive and negative predictive values for SR-12 of 78%, 96%, 78% and 96%, respectively. All 5 patients with HBsAg≤2 log IU/ml and reduction >1 log at the end of treatment achieved SR-12 and all 40 patients with HBsAg>2 log IU/ml and reduction ≤1 log did not have SR-12. The cumulative probability of sustained response and HBsAg clearance at 5 years among patients with HBsAg≤2 log IU/ml were 88% and 72%, respectively, that among patients with HBsAg reduction >1 log were 74% and 61%, respectively.

Monitoring of HBsAg level can guide the timing of stopping lamivudine in HBeAg-negative chronic hepatitis B.

In animal studies, expression of hepatitis B virus (HBV) proteins causes hepatic steatosis. We aimed to study the prevalence of fatty liver in people with and without HBV infection in the general population.

We performed a cross-sectional population study in Hong Kong Chinese. Intrahepatic triglyceride content (IHTG) was measured by proton-magnetic resonance spectroscopy.

One thousand and thirteen subjects (91 HBV patients and 922 controls) were recruited. The median IHTG was 1.3% (0.2-33.3) in HBV patients and 2.1% (0-44.2) in controls (p <0.001). Excluding subjects with significant alcohol consumption, the prevalence of nonalcoholic fatty liver disease was 13.5% (95% confidence interval [CI] 6.4%, 20.6%) in HBV patients and 28.3% (95% CI 25.3%, 31.2%) in controls (p=0.003). The fatty liver prevalence differed in HBV patients and controls aged 40-59 years but was similar in those aged 60 years or above. After adjusting for demographic and metabolic factors, HBV infection remained an independent factor associated with lower risk of fatty liver (adjusted odds ratio 0.42; 95% CI 0.20, 0.88; p=0.022). HBV patients also had a lower prevalence of metabolic syndrome (11.0% vs. 20.2%; p=0.034), but the difference was mainly attributed to lower triglyceride levels. Among HBV patients, viral genotypes, HBV DNA level and hepatitis B e antigen status were not associated with fatty liver.

HBV infection is associated with a lower prevalence of fatty liver, hypertriglyceridemia and metabolic syndrome. Viral replication may affect lipid metabolism and this warrants further studies.

Antiviral therapy for hepatitis B virus (HBV) infection is frequently prescribed for patients with chronic HBV infection during surveillance for hepatocellular carcinoma (HCC). In patients who subsequently develop HCC, the impact of antiviral therapy on the outcome of HCC remains unclear.

We aimed to study the impact of antiviral therapy on the survival of patients who developed HCC.

From two prospective surveillance cohorts, the use of antiviral therapy for patients with HCC was retrospectively reviewed. We compared the overall survival, liver function and tumour characteristics between patients with and without antiviral therapy during surveillance. Multivariate analysis was conducted to determine the independent prognostication of antiviral therapy.

During a median follow-up of 10.1 years of 1429 patients, 148 cases of HCC were diagnosed and followed up for a median of 5.7 years. Twenty-nine patients were given antiviral therapy during surveillance and continued treatment after diagnosis of HCC. The median survival of this group of patients was better than the rest of cohorts (hazard ratio: 0.472; 95% CI: 0.25-0.89; P = 0.0191). Use of antiviral therapy remained an independent prognostic factor after adjustment for demographic factors and tumour staging on multivariate analysis. Exploratory analysis revealed that patients who commenced antiviral therapy during surveillance had lower HBV DNA, lower serum alanine transaminase, better hepatic reserves and higher rate of local treatment at diagnosis of HCC.

This study provides evidence that commencement of antiviral therapy during the surveillance period is associated with improvement in overall survival in HBV-related HCC.

We intended to investigate the effects of pre-existing mutations at reverse transcriptase region of hepatitis B virus (HBV) on the occurrence of virological breakthrough (VB) to adefovir dipivoxil (ADV) in patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB).

Ninety-seven patients with LAM-resistant CHB were treated with ADV at a dose of 10 mg daily, and were followed for a median period of 13 months. Just before the initiation of ADV therapy, the whole length of reverse transcriptase region of serum HBV-DNA was sequenced using direct sequencing.

All patients had genotype C HBV and mutations in the YMDD motif, specifically, YIDD (65%), YVDD (28%), or both (7%). The rtL180M and rtL80V/I mutations were identified in 68% and 69%, respectively. The cumulative probability of VB was 19% and 27% at 1 and 2 years, respectively. There was no difference in the occurrence of VB with regard to types of YMDD mutation or rtL80V/I. However, interestingly, patients carrying rtL180M experienced VB during ADV monotherapy more frequently than those not carrying rtL180M (2-year cumulative probability of VB: 37% vs 3% at 2 years, P < 0.01). On multivariate Cox proportional hazards analysis, rtL180M (hazard ratio [HR]: 8.62, 95% confidence interval: 1.08-69.09, P = 0.042) and decrease in HBV-DNA for 1 year of treatment (HR: 0.69, 95% CI: 0.51-0.95, P = 0.024) are independently associated with VB.

The rtL180M mutation of HBV, as well as a small decrease in HBV-DNA after 1 year of treatment might be closely associated with frequent occurrence of virological resistance to ADV in patients with LAM-resistant CHB.

Antiviral drugs against hepatitis B virus are limited by the emergence of drug resistance.

We aimed to study the impact of drug resistance testing on treatment decisions.

In part 1 of this study, consecutive patients with chronic hepatitis B who had antiviral drug resistance testing were studied. Part 2 was a two-step questionnaire survey including ten characteristic case scenarios. Hepatologists were asked about their treatment decisions before and after the knowledge of drug resistance results.

Fifty-one patients underwent drug resistance testing, most of whom were on lamivudine, adefovir dipivoxil or entecavir monotherapy. Thirty-four (67%) patients had drug-resistant mutants detected, 4 (8%) had low viral load, and 13 (25%) harboured wild-type virus. Twenty-nine of 34 (85%) patients harbouring drug-resistant mutants and 9 of 17 (53%) patients with no mutants detected changed their drug regimens (P = 0.038). In part 2, 18 hepatologists completed all two questionnaires. Overall, treatment decision was modified in 52% of cases upon receiving the drug resistance testing results. The detection of rtA181V/I resulted in decision changes in most hepatologists, with the preferred treatment switching from tenofovir to entecavir. When no mutants were detected in partial responders to entecavir monotherapy, most hepatologists chose to increase the dose of entecavir.

Drug-resistant mutations are detected in around two-thirds of chronic hepatitis B patients undergoing drug resistance testing. Drug resistance testing alters management in over half of the cases, and should be considered in all patients with virological breakthrough and suboptimal virological suppression.

In chronic hepatitis B (CHB) patients, adefovir is commonly used as a rescue therapy for lamivudine resistance, but often results in incomplete virological suppression.

To study the factors predicting response to adefovir rescue, and the treatment response of tenofovir and entecavir in suboptimal responders to adefovir in CHB patients.

Chronic hepatitis B patients who took adefovir for at least 6 months for lamivudine resistance were studied. Early virological response was defined as undetectable HBV DNA at month 6. Maintained virological response was defined as undetectable HBV DNA till the last follow-up.

Among 136 patients on adefovir for 39 (5-117) months, 30 (22%) had early virological response. The 3-year cumulative probability of maintained virological response was similar between patients on adefovir monotherapy (n = 53, 57.9%) and those on combination of lamivudine and adefovir treatment (n = 83, 56.5%). The month 6 HBV DNA was the only independent factor associated with maintained virological response (adjusted hazard ratio 0.49, 95% confidence interval 0.37-0.65, P < 0.001). Twenty-six of 30 (87%) early responders and 36 of 106 (34%) non-early responders had maintained virological response on adefovir (P < 0.001). Among 106 non-early responders, 18 and 11 were switched to tenofovir and entecavir, respectively. The 1-year cumulative probability of maintained virological response was higher in patients switched to tenofovir (87.5%) than those switched to entecavir (37.5%; P = 0.048) or continued with adefovir (8.7%; P < 0.001).

In adefovir rescue for lamivudine resistance, month 6 HBV DNA predicts maintained virological response in CHB patients. Switching to tenofovir achieved best viral suppression among suboptimal responders to adefovir.

We studied whether quantification of serum HBsAg and HBV DNA levels could predict spontaneous HBsAg clearance in patients with negative hepatitis B e antigen (HBeAg).

Serum HBsAg and HBV DNA levels were measured at baseline among a longitudinal cohort of 103 HBeAg-negative patients recruited since 1997.

Twelve (12%) patients developed HBsAg seroclearance after 88 ± 26 months (range, 21-139) of follow-up. At baseline, the serum HBsAg level among patients who cleared HBsAg (1.30 ± 1.27 log IU/mL) was significantly lower than those who did not clear HBsAg (2.96 ± 0.84 log IU/mL; P < .001). The area under receiver operating characteristics (ROC) curve for serum HBsAg to predict HBsAg seroclearance was 0.90 (95% confidence interval [CI], 0.83-0.97; P < .001). Nine (75%) of 12 patients who had HBsAg seroclearance versus 8 (9%) of 91 who remained HBsAg-positive had serum HBsAg ≤100 IU/mL at the baseline (P < .001). An HBsAg cutoff of ≤100 IU/mL had 75% sensitivity and 91% specificity to predict HBsAg seroclearance. Baseline serum HBV DNA could not predict HBsAg seroclearance; the area under ROC curve was 0.64 (95% CI, 0.46-0.81; P = .13).

Single-point serum HBsAg level can predict the chance of HBsAg seroclearance in chronic hepatitis B patients with negative HBeAg.

Role of caffeine consumption in chronic hepatitis B virus (HBV)-infected patients and the interaction with alcohol consumption is unclear.

This study aimed to investigate the relationship between caffeine and alcohol consumption and liver stiffness in chronic HBV-infected patients.

Chronic HBV-infected patients who underwent transient elastography examination in 2006-2008 were studied. Advanced fibrosis was defined as liver stiffness > 9 kPa for patients with normal alanine aminotransferase (ALT) or > 12 kPa for those with elevated ALT according to previous validation study. Caffeine and alcohol consumption was recorded using a standardized questionnaire. Excessive alcohol intake was defined as 30 g/day in men and 20 g/day in women.

The liver stiffness of 1045 patients who completed the questionnaire was 8.3 ± 6.2 kPa. Two hundred and sixteen (20.7%) patients had advanced fibrosis. Ninety-five (19.0%) patients who drank ≥ 1 cup of coffee had advanced fibrosis, compared with 121 (22.2%) patients who drank < 1 cup (P = 0.21). The amount of caffeine intake had positive correlation with the amount of alcohol intake (r(s) = 0.167, P < 0.001). Although 231 (22.1%) patients reported alcohol consumption, only 11 (1%) had excessive alcohol intake. The prevalence of advanced fibrosis among patients with mild to moderate alcohol intake (26, 18.8%) was comparable to that among non-drinkers (190, 21.0%) (P = 0.57).

Caffeine intake does not affect liver stiffness in chronic HBV-infected patients. Patients who drink coffee regularly tend to drink alcohol. Most chronic HBV-infected patients do not have excessive alcohol consumption. The prevalence of advanced fibrosis among mild to moderate alcohol drinkers was low in this population.

Severe acute exacerbation of chronic hepatitis B is a unique clinical presentation with significant morbidity and mortality. Lamivudine was used in most previous studies, but the drug was limited by the development of resistance. Our objective is to study the safety and efficacy of entecavir in patients with severe acute exacerbation.

Consecutive patients with severe acute exacerbation of chronic hepatitis B were recruited from 1998 to 2009. All patients had serum alanine aminotransferase and bilirubin increased beyond 10 and 3 times the upper limit of normal, respectively. The primary endpoint was overall mortality at week 48. Virological and biochemical responses were also studied.

Thirty-six patients and 117 patients were treated with entecavir and lamivudine, respectively. By week 48, 7 (19%) patients in the entecavir group and 5 (4%) patients in the lamivudine group died (adjusted hazard ratio 5.1, 95% confidence interval 1.5-17.2, p=0.010). Similarly, the entecavir group had higher liver-related mortality (adjusted hazard ratio 4.0, 95% confidence interval 1.0-15.7, p=0.044). Despite a lower prevalence of cirrhosis, more patients in the entecavir group developed prolonged jaundice, hepatic encephalopathy, and ascites. Entecavir resulted in more rapid and complete viral suppression, with 71% of patients achieving undetectable hepatitis B virus (HBV) DNA at week 48, compared to 40% in the lamivudine group (p=0.007). However, rapid HBV DNA reduction at week 4 was associated with prolonged jaundice.

Entecavir treatment is associated with increased short-term mortality in patients with severe acute exacerbation of chronic hepatitis B but achieves better virological response in the long run.

On-treatment predictors of response to peginterferon can guide individualization of therapy in chronic hepatitis B virus infection.

To investigate the use of serum hepatitis B surface antigen quantification to predict sustained response.

Hepatitis B e antigen-positive chronic hepatitis B patients who received peginterferon for 32-48 weeks with or without lamivudine combination were studied. Sustained response was defined as hepatitis B e antigen seroconversion and chronic hepatitis B virus DNA <10 000 copies/mL until 12 months post-treatment.

Twenty-one of 92 (23%) patients achieved sustained response. At month 6, the area under receiver operating characteristics curve for hepatitis B surface antigen to predict sustained response was 0.77 (95% confidence interval 0.65-0.89, P < 0.001). An hepatitis B surface antigen cutoff at 300 IU/mL at month 6 could give the maximum combination of sensitivity (62%) and specificity (89%) to predict sustained response. Nine of 21 (43%) sustained responders vs. 9 of 71 (13%) nonsustained responders had >1 log hepatitis B surface antigen reduction at month 6 (P < 0.001). Combined hepatitis B surface antigen ≤ 300 IU/mL and >1 log reduction at month 6 had sensitivity, specificity, positive and negative predictive values of 43%, 96%, 75% and 85% to predict sustained response, respectively.

On-treatment serum hepatitis B surface antigen can predict response to peginterferon therapy in chronic hepatitis B.

Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is responsible for viral persistence. This study aimed to investigate the serum surrogate markers for cccDNA and to evaluate the intrahepatic viral events associated with disease activity in HBeAg-negative chronic hepatitis B patients. Thirty-three treatment-naïve patients with a negative HBeAg who had a liver biopsy were studied. Active disease was defined as a serum alanine aminotransferase >40 IU/L and a serum HBV DNA >10,000 copies/ml. This study showed significant correlation between serum HBV DNA and both log cccDNA (r = 0.41, P = 0.018) and log total intrahepatic HBV DNA (r = 0.71, P < 0.0001). No significant correlation was observed between serum HBsAg and log cccDNA (P = 0.15) or log total intrahepatic HBV DNA (P = 0.97). Fourteen and 19 patients had inactive and active disease, respectively. The median log cccDNA and log total intrahepatic HBV DNA (copies/10(6) cells) were significantly higher in patients with active disease compared with those with inactive disease (4.11 vs. 3.53, P = 0.03 and 5.46 vs. 4.64, P < 0.001, respectively). The HBV replicative efficiency, defined as the ratio of serum HBV DNA to cccDNA, was approximately 20% higher in patients with active disease. No significant difference was observed in the HBsAg levels and the ratio of serum HBsAg to cccDNA between the two groups. In conclusion, serum HBV DNA, but not HBsAg, reflects the amount of cccDNA and the replication efficiency of HBV in patients with HBeAg-negative chronic hepatitis B.

Serum hepatitis B surface antigen (HBsAg) quantification has been suggested to reflect the concentration of covalently closed circular DNA in the liver. We aimed to investigate the HBsAg levels at different stages of chronic hepatitis B and the changes in HBsAg level during the natural progression of disease. One hundred seventeen untreated patients with chronic hepatitis B were studied with longitudinal follow-up for 99 ± 16 months. HBsAg quantification was performed at the first visit, the last visit, and three visits at each quartile during the follow-up. At the first visit, HBsAg level was higher among patients who were hepatitis B e antigen (HBeAg)-positive (N = 49) than those who were HBeAg-negative (N = 68) (4.01 ± 0.91 log IU/mL versus 2.73 ± 1.25 log IU/mL, P < 0.001). HBsAg level was persistently high at approximately 5 log IU/mL among patients in the immune tolerance phase (N = 7). The HBsAg levels among patients with HBeAg-positive active disease (N = 25) or sustained HBeAg seroconversion (N = 17) were comparable at approximately 3-4 log IU/mL. The HBsAg levels among patients who were HBeAg-negative tended to be higher among patients with active (N = 46) than those with inactive disease (N = 22). The median HBsAg levels decreased in HBeAg-negative patients with active and inactive disease by 0.041 log IU/mL/year and 0.043 log IU/mL/year, respectively. Twenty-two (17%) patients had HBsAg reduction >1 log IU/mL at the last visit; most of them showed reduced hepatitis B virus DNA, and eight had HBsAg loss.

HBsAg remained stable in HBeAg-positive patients and tended to reduce slowly in HBeAg-negative patients. Reduction of HBsAg for >1 log IU/mL could reflect improved immune control.

The prognosis of patients with hepatitis B virus (HBV)-associated acute on chronic liver failure (ACLF) is extremely poor.

This study was designed to evaluate the efficacy and safety of nucleoside analogue treatment of patients with HBV-associated ACLF.

We used a retrospective review of eligible patients from April 2006 to December 2008. Eligible subjects received 0.5 mg entecavir daily until October 2009 (group A), 100 mg lamivudine daily until October 2009 (group B), or no nucleoside analogue (group C). The primary endpoints were three-month survival and the rate of recurrence of HBV-associated ACLF. The secondary endpoints were HBV DNA levels, liver function, the model of end-stage liver disease (MELD) score, and adverse events.

A total of 104 consecutive patients were recruited, and 33, 34, and 37 patients were randomly allocated to groups A, B, and C, respectively. Although no significant difference in three-month survival was observed, levels of HBV DNA and rates of recurrence of HBV-associated ACLF were lower. Liver function and MELD score were not significantly improved despite significantly reduced HBV DNA levels.

These data indicated that nucleoside analogue treatment did not improve the short-term prognosis of patients with HBV-associated ACLF although it was efficacious and safe in the management of HBV DNA levels. Intriguingly and importantly, continuous nucleoside analogue treatment can significantly reduce the rate of recurrence, which might be indicative of the further benefit of long-term survival.

Approximately 30%-40% of patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B treated with peginterferon and/or lamivudine achieve HBeAg seroconversion 6 months after the end of treatment. The durability and long-term effect of treatment are unknown. In this study, 85 HBeAg-positive patients who received peginterferon alfa-2b 1.5 microg/kg/week for 32 weeks and lamivudine 100 mg/day for 52 or 104 weeks were prospectively followed for 6.1 +/- 1.7 years posttreatment. Twenty-five (29%) patients had virologic response (HBeAg seroconversion and HBV DNA <10,000 copies/mL) at 5 years. The rate of HBeAg seroconversion rose progressively from 37% at the end of treatment to 60% at 5 years. Twenty-seven (32%) and 11 (13%) patients had undetectable HBV DNA (<100 copies/mL) at the end of peginterferon treatment and at 5 years, respectively. Two (2.4%) patients achieved hepatitis B surface antigen (HBsAg) seroclearance at 2.6 and 84 months posttreatment. Among virologic responders at the end of treatment, 82% and 57% and sustained HBeAg seroconversion and virologic response at 5 years. End-of-treatment serum quantitative HBsAg was significantly lower in patients with sustained virologic response at 5 years (median 1,431 IU/mL versus 2,689 IU/mL [P = 0.041]). At the last follow-up, the liver stiffness measurement by transient elastography was 5.8 +/- 2.7 kPa. Only two patients had liver stiffness suggestive of advanced fibrosis. Week 16 HBV DNA, end-of-treatment HBeAg seroconversion, and undetectable HBV DNA were independent factors associated with virologic response at 5 years. The duration of concomitant lamivudine treatment had no impact on any long-term response.

Peginterferon has high durability in HBeAg-positive chronic hepatitis B patients with end-of-treatment virologic response.

Hepatitis B virus (HBV) infection is an important etiology for hepatocellular carcinoma (HCC). We aim to develop a simple clinical score in predicting the risk of HCC among HBV carriers.

We first evaluated 1,005 patients and found that the following five factors independently predicted HCC development: age, albumin, bilirubin, HBV DNA, and cirrhosis. These variables were used to construct a prediction score ranging from 0 to 44.5. The score was validated in another prospective cohort of 424 patients.

During a median follow-up of 10 years, 105 patients (10.%) in the training cohort and 45 patients (10.6%) in the validation cohort developed HCC. Cutoff values of 5 and 20 best discriminated HCC risk. By applying the cutoff value of 5, the score excluded future HCC development with high accuracy (negative predictive value = 97.8% and 97.3% in the training and validation cohorts, respectively). In the validation cohort, the 5-year HCC-free survival rates were 98.3%, 90.5%, and 78.9% in the low-, medium-, and high-risk groups, respectively. The hazard ratios for HCC in the medium- and high-risk groups were 12.8 and 14.6, respectively.

A simple prediction score constructed from routine clinical and laboratory parameters is accurate in predicting HCC development in HBV carriers. Future prospective validation is warranted.

Chronic hepatitis B patients with diabetes and metabolic syndrome are at increased risk of cirrhosis and hepatocellular carcinoma, but the underlying mechanism is unclear. Our objective was to test whether dysregulation of adipokines contributes to liver injury. We also studied whether viral factors affected adipokines, insulin resistance, and hepatic steatosis.

A prospective cohort of 266 chronic hepatitis B patients undergoing liver biopsy was studied. Fasting blood was taken for the analysis of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), adiponectin, leptin, and resistin. Insulin resistance was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR). Factors associated with significant necroinflammation and cirrhosis were identified.

Histological activity index was correlated with serum TNF-alpha (R=0.40, P<0.0001) and IL-6 (R=0.32, P<0.0001) but not with adiponectin, leptin, or resistin. By multivariate analysis, TNF-alpha was associated with significant necroinflammation after adjusting for age and viral factors (odds ratio (OR) 1.041, 95% confidence interval (CI) 1.002-1.082, P=0.04). Serum adiponectin had positive correlation with hepatitis B virus DNA (R=0.17, P=0.007) and was decreased in patients with insulin resistance and hepatic steatosis. On the other hand, viral load, hepatitis B e-antigen status, and genotypes had no association with insulin resistance, hepatic steatosis, and the levels of TNF-alpha and IL-6. A total of 68 (25.6%) patients had cirrhosis. HOMA-IR, but not adipokine dysregulation, was independently associated with cirrhosis (OR 1.09, 95% CI 1.02-1.15, P=0.006).

TNF-alpha and/or IL-6 contribute to hepatic necroinflammation in chronic hepatitis B patients. Adiponectin protects against insulin resistance and hepatic steatosis but does not affect liver injury. Adipokines and viral factors contribute to liver injury independently.

Histologic analyses of liver fibrosis have been limited by small sample sizes and the predominance of samples from patients with active hepatitis.

We performed a prospective study of transient elastography in treatment-naive patients with chronic hepatitis B, to investigate the relationship between hepatitis B virus (HBV) genotype and liver fibrosis. A validated liver stiffness measurement algorithm was used to define insignificant fibrosis and advanced fibrosis.

Of 1106 patients, 711 (64%) were older than age 40, 370 (34%) had positive test results for hepatitis B e antigen (HBeAg), and 386 (35%) had increased serum levels of alanine aminotransferase. Of the patients, 524 (49%) had genotype B and 582 (51%) had genotype C HBV infection. Patients with genotype C infection had insignificant fibrosis less often (42% vs 55%; P < .0001) and advanced fibrosis more often (25% vs 19%; P = .015) than those infected with genotype B HBV. The difference in the severity of liver fibrosis between the 2 HBV genotypes was most marked among patients older than age 40 and those who tested negative for HBeAg. The mean age of patients infected by genotype C was greater than that of patients infected by genotype B HBV (41 vs 36 y). Among patients who were older than age 40 and tested negative for HBeAg, those with genotype C infection had higher levels of HBV DNA and alanine aminotransferase than those with genotype B HBV.

Genotype C HBV was associated with more severe liver fibrosis than genotype B HBV, probably because of delayed HBeAg seroconversion and prolonged active disease.

We hypothesized that liver-derived mRNA, such as ALB (albumin) mRNA, would be released into human plasma with liver cell death.

We genotyped ALB mRNA molecules in samples of plasma and whole blood from liver and bone marrow transplant recipients by RNA single-nucleotide polymorphism analysis. Plasma and whole blood ALB mRNA genotypes were compared with the DNA genotypes of the recipients and donors. A reverse-transcription quantitative real-time PCR assay was used to measure plasma ALB mRNA concentrations in 107 patients [hepatocellular carcinoma (HCC), cirrhosis, or chronic hepatitis B (CHB)] and 207 healthy controls.

The RNA genotype data revealed ALB mRNA in plasma to be liver derived, whereas tissue compartments other than the liver also contributed to the ALB mRNA detected in whole blood. Statistically significant increases in plasma ALB mRNA concentrations were observed for HCC, cirrhosis, and active CHB, compared with controls. A cutoff of 835 copies/mL of plasma ALB mRNA identified by ROC curve analysis showed 85.5% diagnostic sensitivity and 92.8% diagnostic specificity for the detection of liver pathologies. Only 21.5% of patients with liver pathologies had increased alanine aminotransferase (ALT) activities, whereas 73.8% had increased plasma ALB mRNA concentrations. Only 48.6% of the HCC patients had increased serum alpha-fetoprotein concentrations, whereas 91.4% had increased plasma ALB mRNA concentrations.

ALB mRNA is liver specific in plasma, but not in whole blood. Plasma ALB mRNA is increased in some liver pathologies and may be more diagnostically sensitive than alpha-fetoprotein and ALT.

It is unclear whether surrogate end points reported in clinical trials correlate with long-term outcome of patients with chronic hepatitis B.

Patients with chronic hepatitis B who participated in any of 4 randomized controlled trials were followed prospectively for liver-related events (hepatocellular carcinoma, ascites, spontaneous bacterial peritonitis, variceal bleeding, liver transplantation, and death). Biochemical (normal ALT levels), virologic (levels of hepatitis B virus DNA below 10,000 copies/mL), and histologic (reduction of necroinflammation grading by 2 points or more with no increase in fibrosis staging) responses were evaluated at the end of each trial.

One hundred ninety-five patients with adequate pretreatment and post-treatment liver biopsies (15 mm long and 6 portal tracts) were followed for 86 months (interquartile range, 77-98). Liver-related events occurred in 12 patients (6%). The risk of liver-related events was lower in patients with biochemical (hazard ratio, 0.21; 95% confidence interval, 0.068-0.68) and histologic (hazard ratio, 0.095; 95% confidence interval, 0.012-0.74) responses. Only 1 patient with a histologic response and 1 patient with an ALT level below Prati's cutoffs (30 IU/L in men and 19 IU/L in women) developed liver-related events. Fifteen of 25 patients (60%) with cirrhosis at baseline had regression of cirrhosis, and none of these patients died or developed liver-related events. In contrast, 3 of these patients still developed liver-related events, despite an initial virologic response, and 2 had virologic breakthrough.

Biochemical and histologic responses, particularly regression of cirrhosis, in patients with chronic hepatitis B are associated with decreased liver-related complications.

Severe acute exacerbation is a unique presentation of chronic hepatitis B characterized by very high alanine aminotransferase level accompanied by jaundice and hepatic decompensation. The underlying pathogenesis is likely related to excessive immune clearance, which may be related to the genotype of hepatitis B virus. The mortality is very high once hepatic encephalopathy develops, but some patients can recover to almost normal liver function in contrast to patients with end-stage liver cirrhosis. This condition should be differentiated from acute hepatitis B and other causes of acute hepatitis must be excluded. Conventional prognostic systems may not be applicable to severe acute exacerbation of chronic hepatitis B. In general, patients who have thrombocytopenia, hyperbilirubinemia and coagulopathy have a higher risk of mortality regardless of the serum alanine aminotransferase levels. There is no evidence that lamivudine treatment can reduce the short-term mortality of severe acute exacerbation. However, patients with severe acute exacerbation tend to have a higher rate of maintained virological response, higher rate of hepatitis B e antigen seroconversion and low rate of drug resistance on extended lamivudine treatment as compared to other chronic hepatitis B patients. Virological relapse and severe hepatitis reactivation is common after treatment cessation and therefore long-term antiviral treatment is recommended. Liver transplantation, particularly living donor liver transplantation, should be considered for patients who develop hepatic failure secondary to severe acute exacerbation.

The proposed cut-off values for the degree of fibrosis as assessed by liver stiffness measurement (LSM) might not be applicable in severe acute exacerbation of chronic hepatitis B (CHB). We aimed to assess the effect of necroinflammatory activity on LSM in this condition.

We prospectively recruited consecutive patients with severe acute exacerbation of CHB (alanine aminotransferase or ALT > 10x upper limit of normal). The relationship of ALT levels and LSM were serially assessed and liver biopsy was carried out after ALT normalization.

Eleven patients (10 male, median age 43 years) were followed up for 25 weeks; nine patients received antiviral therapy. Overall, LSM was positively correlated with ALT levels (r = 0.67, P < 0.001). At initial presentation, the median serum ALT and LSM was 1136 (581-2210) IU/L and 26.3 (11.1-33.3) kPa. A progressive reduction in LSM was observed during subsequent visits in parallel with the reduction of ALT levels. At the last visit, the median ALT was 27 (11-52) IU/L and LSM was 7.7 (4.7-10.8) kPa. Among the five patients who had liver biopsy carried out at week 25, four patients had F2 fibrosis (LSM 5.7-8.1 kPa) and one patient had F3 fibrosis (LSM 8.6 kPa).

LSM using transient elastography with the current proposed cut-off values might misdiagnose liver cirrhosis in patients suffering from severe acute exacerbation of CHB. LSM should be assessed after normalization of ALT levels in order to accurately assess the degree of fibrosis.

We aimed to investigate the impact of hepatitis B virus (HBV) DNA on the development of hepatocellular carcinoma (HCC). We conducted a case/control study based on 506 chronic HBV patients followed up since 1997. Forty-one patients developed HCC, and each of them was age and gender matched with two simultaneously recruited controls without HCC. HBV DNA was measured at the initial visit, at yearly intervals, and at the last visit. Patient age at the time of HCC development was 55 +/- 9 years. Forty-nine (40%) patients experienced antiviral treatment. The median time from diagnosis to the development of HCC was 17 months, and the control patients were followed for 92 months. At the trough level (defined as lowest level among all studied visits), more (27 patients; 66%) HCC patients had HBV DNA levels of >10,000 copies/ml than the controls (17 patients; 21%). The area under the receiver operating characteristic curve of the trough log HBV DNA level for HCC was 0.79 (95% confidence interval [CI], 0.69 to 0.89). Trough log HBV DNA (odds ratio, 11.4; 95% CI, 3.6 to 37.6; P < 0.0001) and liver cirrhosis (odds ratio, 11.4; 95% CI, 3.6 to 36.2; P < 0.0001) levels were independently associated with HCC after an adjustment for age, gender, antiviral treatment, and HBV genotype. The difference in the trough HBV DNA level was more obvious among untreated patients (5.7 +/- 1.4 log copies/ml in HCC patients versus 3.2 +/- 1.3 log copies/ml in control patients; P < 0.0001) than among those who had received antiviral treatment (3.0 +/- 1.4 log copies/ml in HCC patients versus 2.5 +/- 0.9 log copies/ml in control patients; P = 0.38). A high trough HBV DNA level was associated with a higher risk of HCC. Whether antiviral treatment could prevent HCC was uncertain.

Lamivudine (LAM) resistance is frequently associated with various types of genomic changes in hepatitis B virus (HBV)-DNA including YMDD mutations (rtM204V/I). We intended to examine the effects of these genotypic variants on the antiviral efficacy of adefovir dipivoxil (ADV) therapy.

A total of 97 chronic hepatitis B (CHB) patients with YMDD mutants who had been treated with ADV for >12 months were analysed. Mutations of the entire polymerase domain of HBV were determined by direct sequencing.

All the 97 patients had genotype C HBV associated with rtM204V/I mutations; 63 (65%) rtM204I, 27 (28%) rtM204V and seven (7%) both. The rtL80V/I and rtL180M variants were identified in 66 (68%) and 67 (69%) patients respectively. The rtM204I and rtM204V variants were strongly associated with rtL80V/I and rtL180M respectively (P<0.01). There was no difference in antiviral response at 12 months after ADV therapy between patients in relation to the type of YMDD mutation or the presence of rtL180M. However, interestingly, after ADV therapy for 12 months, patients with rtL80V/I achieved a much smaller reduction in serum HBV-DNA titre than those without it (mean, -3.43 vs. -4.43 log(10) copies/ml; P=0.018). In addition, patients with rtL80V/I had lower rates of undetectable HBV-DNA (20 vs. 26%), alanine aminotransferase normalization (70 vs. 81%) and HBeAg loss (16 vs. 26%) than those without it, although none of these differences was statistically significant.

These results provide evidence that rtL80V/I variants of HBV may be associated with a poor antiviral response to ADV in CHB patients with YMDD mutants.

In Asia Pacific countries, lamivudine is used frequently as the sole prophylaxis for hepatitis B virus (HBV) recurrence after liver transplantation due to financial consideration. The aim was to evaluate the long-term outcome of lamivudine monoprophylaxis with adefovir salvage for liver transplantation in chronic hepatitis B. Consecutive chronic hepatitis B patients who received liver transplantation from 1999 to 2003 and with at least 12 months follow up were studied. Lamivudine monotherapy was used for antiviral prophylaxis and adefovir was added as salvage treatment for recurrence of HBV. Twenty-four patients were followed up for 272 (76-372) weeks post-liver transplantation. HBV recurrence developed in seven patients with cumulative probabilities of 8%, 13%, 28%, 35%, 35%, and 49% in 1, 2, 3, 4, 5, and 6 years. At the time of recurrence of HBV, the HBV DNA level was 910,244 (363 to 9 x 10(8)) copies/ml. On direct sequencing, four patients had rtM204I mutation and three patients HBV DNA levels were too low for sequencing. Six patients had elevated ALT (two patients had ALT >1,000 IU/L and jaundice) but none had hepatic encephalopathy. After adefovir treatment for 150 (91-193) weeks, six (86%) patients had normal ALT. HBV DNA was undetectable in two (29%) patients, 100-1,000 copies/ml in two (29%) patients and 10,000-100,000 copies/ml in three (43%) patients on last visit. No genotypic resistance to adefovir was detected. Lamivudine followed by adefovir salvage is effective for prophylaxis of recurrence of HBV after liver transplantation up to 7 years.

We analyzed the clinical factors associated with advanced liver fibrosis in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients.

We prospectively recruited treatment-naive HBeAg-positive patients for liver stiffness measurement (LSM) by transient elastography. Insignificant and advanced fibrosis was defined as an LSM of 6.0 kPa or less, and greater than 9.0 kPa for patients with alanine aminotransferase (ALT) levels less than or equal to the f upper limit of normal (ULN), and 7.5 kPa or less and greater than 9.0 kPa for those with ALT levels between 1 and 5 x ULN, respectively, based on a previous study with histologic validation.

A total of 453 patients were studied. Among 74 patients who also had a liver biopsy, the cut-off levels for advanced fibrosis had 95% specificity. Age and ALT level, but not hepatitis B virus DNA level, were associated independently with LSM. Based on receiver operating characteristics curve analysis, patients older than 35 years had the highest specificity for advanced fibrosis. The risk of advanced fibrosis increased in patients with an ALT level greater than 0.5 x ULN. Among the 47 patients who were older than 35 years with an ALT level of 0.5 x ULN or less, 39 (83%) had an LSM suggestive of insignificant fibrosis, and 1 (2%) had advanced fibrosis. Among the 217 patients who were older than 35 years with an ALT level greater than 0.5 x ULN, 61 (28%) had LSM indicating insignificant fibrosis, and 80 (37%) had advanced fibrosis.

Risk of advanced liver fibrosis increased in HBeAg-positive patients older than 35 years of age with an ALT level greater than 0.5 x ULN.

The aim of this study is to know the liver stiffness measurement (LSM) cutoffs for different stages of liver fibrosis in chronic hepatitis B (CHB) and to investigate the effect of alanine aminotransferase (ALT) on LSM. We prospectively studied consecutive CHB patients undergoing liver biopsy and transient elastography examinations. Diagnostic performance of LSM for different degrees of liver fibrosis was evaluated. One hundred and sixty-one CHB patients with adequate liver biopsy sample size were studied. Area under receiver operating characteristics curves of LSM for no fibrosis (F0 vs F1-4), bridging fibrosis (F0-2 vs F3-4) and liver cirrhosis (F0-3 vs F4) was 0.80 (95% CI: 0.68-0.92), 0.87 (95% CI: 0.82-0.93) and 0.93 (95% CI: 0.89-0.97) respectively. For liver cirrhosis, these optimal cutoff values were 8.4 kPa (98% sensitivity), 9.0 kPa (maximum sum of sensitivity and specificity), 13.4 kPa (94% specificity) and 13.4 kPa (maximum diagnostic accuracy, 85%) respectively. Patients with the same fibrosis staging but higher ALT levels tend to have higher LSM, and the diagnostic performance for low stage fibrosis was most seriously affected when ALT was elevated. Different LSM cutoff values and algorithms were derived for normal and elevated ALT levels. Based on these algorithms, liver biopsy can be avoided in 62% and 58% of patients with normal and elevated ALT respectively. In conclusion, transient elastography is a reasonable noninvasive tool to substitute liver biopsy among the lowest and highest risk patients for the assessment of liver fibrosis.

We aimed to investigate the relationship between serum hepatitis B virus (HBV) DNA and alanine transaminase (ALT) levels and the risk of cirrhosis in a large cohort of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients based on transient elastography.

We prospectively studied treatment-naive HBeAg-negative patients recruited based on territory-wide referrals. We defined possible cirrhosis and probable cirrhosis with two different cutoffs according to the results from a subgroup of patients with histologic proof.

One thousand one hundred ninety-seven patients with successful liver stiffness measurement (LSM) were studied. In the subgroup of 100 patients with liver biopsy, LSM of > or =8.4 kiloPascal (kPa) had a sensitivity of 90% and LSM of > or =13.4 kPa had a specificity of 94% for liver cirrhosis. Possible and probable cirrhosis were defined as a LSM value > or =8.4 kPa and > or =13.4 kPa, and were present in 31% and 11% of the patients, respectively. The risk of cirrhosis was significantly increased when ALT level was >0.5x upper limit of normal (ULN) or serum HBV DNA >4 log(10) copies/mL. Among patients who have ALT < or =0.5 x ULN and HBV DNA < or =4 log(10) copies/mL, 10% (26/264) and 3% (7/264) had possible and probable cirrhosis respectively, which were significantly lower when compared with 34% (329/887, P < 0.001) and 14% (125/887, P < 0.001) of those who had higher ALT and HBV DNA levels.

Liver cirrhosis was common among HBeAg-negative CHB patients. Patients with ALT levels >0.5 x ULN and/or serum HBV DNA >4 log(10) copies/mL have higher risk of cirrhosis and need further assessment for antiviral therapy.